Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines

ABSTRACT

The invention relates to an improved process for preparing enantiomerically pure 8-(3-aminopiperidin-1-yl)-xanthines.

The invention relates to an improved process for preparing chiral8-(3-aminopiperidin-1-yl)-xanthines, their enantiomers and theirphysiologically tolerated salts.

8-(3-aminopiperidin-1-yl)-xanthines of the following general structure

in which R¹ is, for example, an optionally substituted arylmethyl groupor an optionally substituted heteroarylmethyl group, R² is, for example,an alkyl group and R³ is, for example, an optionally substituted benzylgroup or a straight-chain or branched alkenyl or alkinyl group arealready known from the international applications WO 02/068420, WO04/018468, WO 04/018467, WO 2004/041820 and WO 2004/046148, in whichcompounds having valuable pharmacological properties are described,which include in particular an inhibiting action on the activity of theenzyme dipeptidylpeptidase IV (DPP-IV). Therefore, compounds of thistype are suitable for preventing or treating disorders or states whichare connected with an increased DPP-IV activity or which can beprevented or alleviated by reduction in the DPP-IV activity, especiallyof diabetes mellitus type I or type II, prediabetes, or reduction ofglucose tolerance.

WO 04/018468 discloses a preparation process in which8-(3-aminopiperidin-1-yl)-xanthines are prepared by deprotecting acorresponding tert.-butyloxycarbonyl-protected derivative of the generalformula (II).

In this process, impurities which were difficult to remove, especiallyon the industrial scale, occurred, and are attributable to theprotecting group used. The process was therefore unsuitable for theindustrial preparation of 8-(3-aminopiperidin-1-yl)-xanthines,especially for medicament production with its strict demands on purity.Furthermore, the method had the disadvantage that the preparation of theenantiomerically pure precursor3-(tert.-butyloxycarbonylamino)piperidine is complicated and expensive.However, enantiomerically pure active ingredients are to be preferredfor the pharmaceutical application owing to the risk of side effects andfor the reduction of the dose to a minimum. These circumstances countagainst the suitability of the known process for the industrialpreparation of enantiomerically pure8-(3-aminopiperidin-1-yl)-xanthines.

In the light of the above-described disadvantages of the knownpreparation process, it is an object of the present invention to providea process which allows the preparation of enantiomerically pure8-(3-aminopiperidin-1-yl)-xanthines using readily obtainable startingmaterials in high chemical and optical purity and without greattechnical cost and inconvenience. This novel process should also besuitable for synthesis on the industrial scale and thus for commercialapplication.

This object is achieved by the process according to the invention forpreparing chiral 8-(3-aminopiperidin-1-yl)-xanthines. In addition tohigh yield industrial performance, very good chemical and opticalpurities are further advantages of the inventive synthetic route.

According to the process of the present invention, the appropriatexanthine precursor (III) is reacted according to scheme 1 withenantiomerically pure or racemic 3-(phthalimido)piperidine in suitablesolvents at temperatures of 20 to 160° C.; preferably of 8 to 140° C.The solvents used may, for example, be tetrahydrofuran (THF), dioxane,N,N-dimethylformamide (DMF), dimethylacetamide (DMA),N-methyl-2-pyrrolidone (NMP) or dimethyl sulphoxide (DMSO). Preferenceis given to using NMP. Subsequently, the phthalyl protecting group isdetached by processes known per se. Possible detachment methods aredescribed, for example, by T. W. Greene in “Protective Groups in OrganicSynthesis”, Wiley 1981 on page 265 (for example hydrazine in ethanol).

In the abovementioned formulae,

X is a leaving group selected from the group of the halogens, forexample a fluorine, chlorine or bromine atom, or of the sulphonicesters, for example a phenyl-sulphonyloxy, p-toluenesulphonyloxy,methylsulphonyloxy or trifluoromethylsulphonyloxy group,

R¹ is a phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridinylmethyl,pyrimidinyl-methyl, quinolinylmethyl, isoquinolinylmethyl,quinazolinylmethyl, quinoxalinylmethyl, naphthyridinylmethyl orphenanthridinylmethyl group in which the aromatic or heteroaromaticmoiety is in each case mono- or disubstituted by R_(a), where thesubstituents may be identical or different and

R_(a) is a hydrogen, fluorine, chlorine or bromine atom or a cyano,methyl, trifluoromethyl, ethyl, phenyl, methoxy, difluoromethoxy,trifluoromethoxy or ethoxy group,

or two R_(a) radicals, when they are bonded to adjacent carbon atoms,may also be an —O—CH₂—O— or —O—CH₂—CH₂—O— group,

R² is a methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl groupand

R³ is a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butin-1-yl,2-fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl,2-methylbenzyl, 2-(trifluoromethyl)benzyl or 2-cyanobenzyl group.

The process is preferable for those compounds in which

X is a chlorine or bromine atom,

R¹ is a phenylcarbonylmethyl, benzyl, naphthylmethyl, pyridinylmethyl,pyrimidinyl-methyl, quinolinylmethyl, isoquinolinylmethyl,quinazolinylmethyl, quinoxalinyl-methyl or naphthyridinylmethyl group inwhich the aromatic or heteroaromatic moiety is in each case mono- ordisubstituted by R_(a), where the substituents may be identical ordifferent and

R_(a) is a hydrogen, fluorine or chlorine atom or a cyano, methyl,ethyl, methoxy or ethoxy group,

R² is a methyl, ethyl, propyl, isopropyl, cyclopropyl or phenyl groupand

R³ is a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butin-1-yl,2-fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl,2-methylbenzyl, 2-(trifluoromethyl)benzyl or 2-cyanobenzyl group.

The process is more preferable for those compounds in which

X is a chlorine or bromine atom,

R¹ is a cyanobenzyl, (cyanopyridinyl)methyl, quinolinylmethyl,(methylquinolinyl)methyl, isoquinolinylmethyl,(methylisoquinolinyl)methyl, quinazolinylmethyl,(methylquinazolinyl)methyl, quinoxazinylmethyl,(methylquinoxalinyl)methyl, (dimethylquinoxalinyl)methyl ornaphthyridinylmethyl group,

R² is a methyl, cyclopropyl or phenyl group and

R³ is a 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butin-1-yl,2-chlorobenzyl, 2-bromobenzyl or 2-cyanobenzyl group,

but in particular for the compounds1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)-xanthine,1-[(3-methylisoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)-xanthineand1-[(3-cyanopiperidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)-xanthine,where X is bromine.

Preference is given in each case to using (R)-3-(phthalimido)piperidineas a reagent. The preparation of the compounds of the formula (III) hasbeen described in the literature which has already been cited above andis effected by processes known per se.

The invention further provides a process for preparing optically active3-(phthalimido)piperidine. In this process, 3-aminopyridine is initiallyhydrogenated by means of processes known per se. The thus obtainedracemic 3-aminopiperidine is then converted to the correspondingphthalimide by means of phthalic anhydride. The (R) enantiomer can beprecipitated selectively out of the solution of the racemic, crudephthalimide (IV) by means of D-tartaric acid. It is also possible toobtain the (S) enantiomer of (IV) in a simple manner from the motherliquor of this salt precipitation by adding L-tartaric acid, withoutpreceding removal of the excess of D-tartaric acid still present in themother liquor.

This extremely simple enantiomeric separation of the compound of theformula (IV) is surprising to those skilled in the art. The racemic basefrom the hydrogenation reaction does not have to be purified beforehandfor this purpose. The process works without any problem even on theindustrial scale.

In addition, the unexpectedly clean reaction of 3-aminopiperidine withphthalic anhydride is surprising per se, since, according to theliterature (for example U.S. Pat. No. 4,005,208, especially Example 27),mixtures would be expected which, in addition to the desired product,comprise derivatives in which the ring nitrogen atom is acylated.

The examples which follow will illustrate the invention in greaterdetail:

EXAMPLE 1 D-Tartaric Acid Salt of the R Enantiomer of3-(phthalimido)piperidine

a. Hydrogenation:

10.00 kg (106.25 mol) of 3-aminopyridine, 500 g of technical-gradeactivated carbon and 65 litres of acetic acid are initially charged in ahydrogenation reactor. 50 g of Nishimura catalyst (a commerciallyavailable rhodium/platinum mixed catalyst) are added slurried in 2.5litres of acetic acid and flushed in with 2.5 litres of acetic acid.Hydrogenation is effected at 50° C. and 100 bar of hydrogen pressureuntil hydrogen uptake stops and post-hydrogenation is subsequentlyeffected at 50° C. for 30 minutes. The catalyst and the activated carbonare filtered off and washed with 10 litres of acetic acid. The productsolution is reacted further without purification.

The reaction also proceeds under less severe pressures.

b. Acylation

15.74 kg (106.25 mol) of phthalic anhydride are initially charged in thereactor and admixed with the filtrate from the hydrogenation. It isflushed in with 7.5 litres of acetic acid and the reaction mixture issubsequently heated to reflux, in the course of which approx. 30% of theacetic acid used is distilled off within one hour. The reaction solutionis cooled to 90° C. The product solution is reacted further withoutpurification.

c. Optical resolution

A solution, heated to 50° C., of 11.16 kg of D(−)-tartaric acid (74.38mol) in 50 litres of absolute ethanol is metered into the acylationreaction solution at 90° C. It is flushed in with 10 litres of absoluteethanol and stirred at 90° C. for 30 minutes, in the course of which theproduct crystallizes. After cooling to 5° C., the product wascentrifuged off and washed with absolute ethanol. The product solutionis reacted further without purification.

d. Recrystallization

The moist crude product is heated to reflux in a mixture of 50 litres ofacetone and 90 litres of water until a solution has formed.Subsequently, the solution is cooled to 5° C., in the course of whichthe product crystallizes out. The suspension is stirred at 5° C. for 30minutes, and the product is centrifuged off and finally washed with amixture of 20 litres of acetone and 10 litres of water. The mixture isdried at 45° C. in a drying cabinet under inertization.

Yields: 11.7-12.5 kg (29-31% of theory)

EXAMPLE 2 Synthesis of1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-aminopiperidin-1-yl)-xanthinea. 2-Chloromethyl-4-methylquinazoline

10.00 kg (73.98 mol) of 2-aminoacetophenone are initially charged and24.5 litres of 1,4-dioxane are added. The solution, cooled to 10° C., isadmixed with 16.72 kg (458.68 mol) of hydrogen chloride by blanketing.The reaction mixture warms up to 22-25° C. At this temperature, furtherhydrogen chloride is blanketed in. From about half of the totalblanketing amount, the mixture is cooled to −10° C. and blanketing iscontinued. Subsequently, the suspension formed is left to stand at −10°C. overnight. A solution of 6.70 kg (88.78 mol) of chloroacetonitrile in2.5 litres of 1,4-dioxane is added at −10° C. within one hour. The feedvessel is flushed with 2 litres of 1,4-dioxane. Afterwards, the reactorcontents are warmed to 6° C. and stirred for a further approx. 2 hours.

A further reactor is initially charged with a mixture of 122 litres ofwater and 62.04 kg (775.31 mol) of sodium hydroxide solution (50%) andcooled to 6° C. The reaction mixture from the first reactor is added inportions. The internal temperature is not more than 11° C. Subsequently,the first reactor is flushed first with 6 litres of 1,4-dioxane and thenwith 6 litres of water. The resulting suspension is stirred at 5° C. fora further 30 minutes. The product is centrifuged off, washed with 41litres of water and dried at 35° C. in a drying cabinet underinertization.

Yield: 10.5-12.1 kg (74-85% of theory)

b.1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-bromoxanthine

10.00 kg (33.66 mol) of 3-methyl-7-(2-butin-1-yl)-8-bromoxanthine, 7.13kg (37.02 mol) of 2-chloromethyl-4-methylquinazoline, 3.92 kg (37.02mol) of anhydrous sodium carbonate and 30 litres ofN-methyl-2-pyrrolidone are initially charged in the reactor. The reactorcontents are heated to 140° C. and stirred at 140° C. for 2 hours. Afterthe reaction has ended, the reaction mixture is cooled to 80° C. anddiluted with 60 litres of 96% ethanol and subsequently at 70° C. with 55litres of water. At 60° C., 4.04 kg (67.32 mol) of acetic acid aremetered in and flushed in with 5 litres of water. The resultingsuspension is stirred at 60° C. for 30 minutes, then cooled to 23° C.and stirred for a further 30 minutes. Subsequently, the product iscentrifuged off and washed first with a mixture of 20 litres of 96%ethanol and 20 litres of water, then with 40 litres of 96% ethanol and40 litres of water. Drying is effected at 45° C. in a drying cabinetunder inertization.

Yield: 11.6-12.6 kg (76-83% of theory)

c.1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-phthalimidopiperidin-1-yl)-xanthine

10.00 kg (22.06 mol) of1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-bromoxanthine,12.59 kg (33.09 mol) of 3-(phthalimido)piperidine D-tartrate and 17.5litres of N-methyl-2-pyrrolidone are initially charged in the reactor.The reactor contents are heated to 140° C. After the temperature hasbeen attained, 11.41 kg (88.24 mol) of diisopropylethylamine are meteredin within 20 minutes. The feed vessel is flushed with 2.5 litres ofN-methyl-2-pyrrolidone and the reaction mixture is subsequently stirredat 140° C. for 2 hours. After the reaction has ended, the reactionmixture is cooled to 60° C. and diluted with 80 litres of methanol. Theresulting suspension is stirred at 50° C. for 30 minutes, then cooled to23° C. and stirred for a further 30 minutes. Subsequently, the productis centrifuged off and washed 3 times with 20 litres each time ofmethanol. Drying is effected at 45° C. in a drying cabinet underinertization.

Yield: 12.0-12.5 kg (90-94% of theory)

d.1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-aminopiperidin-1-yl)-xanthine

1800 kg (3 mol) of1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-phthalimidopiperidin-1-yl)-xanthineare heated to 80-85° C. in 18 litres of toluene. Subsequently, 1.815litres (30 mol) of ethanolamine are added to the suspension at 75-80° C.To complete the reaction, the mixture is stirred at 80-85° C. for 2hours, in the course of which the solids go into solution. Subsequently,the phases are separated. The ethanolamine phase is washed twice withwarm toluene (4 litres each time). The combined toluene phases arewashed twice with 8 litres each time of water at 75-80° C. From thetoluene phase, 22 litres of toluene are distilled off under reducedpressure. 4 litres of tert.-butyl methyl ether are metered at 40-50° C.to the resulting suspension and subsequently cooled to 0-5° C. Theproduct is isolated by filtration, washed with tert.-butyl methyl etherand suction-dried. The moist crude substance is subsequently heated toreflux with 5 times the amount of absolute ethanol and the hot solutionis clarified by filtration through activated carbon. After the filtratehas been cooled to 20° C. and crystallization has set in, it is dilutedto double the volume with tert.-butyl methyl ether. The suspension iscooled to 2° C., stirred for a further 2 hours, filtered with suctionand dried at 45° C. in a vacuum drying cabinet.

Yield: 1174 g (83.2% of theory)

e. Alternative Process for Step d

1400 g (2.32 mol) of1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-phthalimidopiperidin-1-yl)-xanthineare initially charged in 4.9 l of tetrahydrofuran and subsequentlyheated to 55-65° C. Subsequently, 350 ml of water and 1433 g (2.32 mol)of ethanolamine are added to the suspension. To complete the reaction,the mixture is stirred at 60-63° C. for a further 3 hours.

Subsequently, 619 ml of 45% sodium hydroxide solution and 3.85 l ofwater are added and the mixture is stirred at 55-65° C. for 30 min.

5.6 l of toluene are then added to the reaction mixture, the mixture isstirred for 15 min and the phases are subsequently separated.

The organic phase is washed with 2.8 l of water at 55-65° C. andsubsequently removed. From the organic phase, 4.2 l are distilled offunder reduced pressure. Subsequently, 1.4 l of methylcyclohexane areadded at 65-75° C., in the course of which the product crystallizes. Thesuspension is stirred at 15-25° C. for 8-16 h and subsequently cooled to0-5° C. The product is isolated by filtration, washed with 4.2 l ofmethylcyclohexane, suction-dried and dried at 35° C. under reducedpressure.

The dried crude substance (991 g) is subsequently heated to reflux with5 times the amount of methanol, activated carbon is added and themixture is filtered. The filtrate is reduced to a volume of 1.5 l bydistilling off methanol. After the filtrate has been cooled to 45-55°C., it is diluted to four times the volume with tert.-butyl methylether. The suspension is cooled to 0-5° C., stirred for 2 hours,filtered with suction, washed with tert.-butyl methyl ether and dried at35° C. in a vacuum drying cabinet.

Yield: 899 g (81.9% of theory)

EXAMPLE 31-[(3-Cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-aminopiperidin-1-yl)-xanthinea. 3-Cyano-2-(chloromethyl)-pyridine

165.5 g (0.98 mol) of 2-hydroxymethyl-3-pyridinecarboxamide are heatedtogether with 270 ml of phosphorus oxychloride to 90-100° C. for 1 hour.The reaction mixture is cooled to room temperature and subsequentlyadded dropwise to approx. 800 ml of water at 50-60° C. After thephosphorus oxychloride has been hydrolyzed, the mixture is neutralizedwith sodium hydroxide solution with cooling, in the course of which theproduct precipitates out. It is filtered off, washed with 300 ml ofwater and subsequently dried at 35-40° C.

Yield: 122.6 g (82% of theory)

Variant to process step a: 3-cyano-2-(chloromethyl)pyridine

20.0 g (131.45 mmol) of 2-hydroxymethyl-3-pyridinecarboxamide aresuspended in 110 ml of acetonitrile and heated to 78° C. Within 15minutes, 60.65 g (395.52 mmol) of phosphorus oxychloride are metered inand the mixture is heated to 81° C. for 2 hours. After cooling at 22°C., the reaction mixture is stirred into 200 ml of water at 40° C. After100 ml of toluene have been added, the mixture is neutralized withsodium hydroxide solution with cooling. After phase separation, theorganic phase is washed with 100 ml of water. Removal of the organicphase and evaporation of the solvent under reduced pressure gives riseinitially to an oily residue which crystallizes on standing.

Yield: 16.66 g (83% of theory)

b.1-[(3-Cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-bromoxanthine

202 g (0.68 mol) of 3-methyl-7-(2-butin-1-yl)-8-bromoxanthine, 188.5 g(1.36 mol) of anhydrous potassium carbonate and 1.68 litres ofN-methyl-2-pyrrolidone are initially charged in the reactor and heatedto 70° C. Subsequently, 119 g (0.75 mol) of2-chloromethyl-3-cyanopyridine in 240 ml of N-methyl-2-pyrrolidine (NMP)are added dropwise. The reactor contents are stirred at 70° C. for 19hours. After the reaction has ended, 2.8 litres of water are added tothe reaction mixture and it is cooled to 25° C. The product is filteredoff, washed with 2 litres of water and dried at 70° C. in a dryingcabinet under inertization.

Yield: 257.5 g (91% of theory)

c.1-[(3-Cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-phthalimidopiperidin-1-yl)-xanthine

230 g (0.557 mol) of1-[(3-cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-bromoxanthine,318 g (0.835 mol) of 3-(phthalimido)piperidine D-tartrate and 1.15litres of N-methyl-2-pyrrolidone are initially charged in the reactor.The reactor contents are heated to 140° C. After the temperature hasbeen attained, 478 ml (2.78 mol) of diisopropylethylamine are metered inwithin 20 minutes and the reaction mixture is subsequently stirred at140° C. for 2 hours. Subsequently, the reaction mixture is cooled to 75°C. and diluted with 720 ml of methanol. Afterwards, 2.7 litres of waterare added at 68-60° C. and the mixture is cooled to 25° C. The productis filtered off and washed with 2 litres of water. Drying is effected at70° C. in a drying cabinet under inertization.

The crude product thus obtained is subsequently stirred at boiling in 1litre of methanol, hot-filtered, washed with 200 ml of methanol andsubsequently dried at 70° C. under inertization.

Yield: 275 g (88% of theory)

d.1-[(3-cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-aminopiperidin-1-yl)-xanthine

412.5 g (0.733 mol) of1-[(3-cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-phthalimidopiperidin-1-yl)-xanthineare heated to 80° C. in 4125 ml of toluene. Subsequently, 445 ml ofethanolamine (7.33 mol) are added to the suspension at 75-80° C. Tocomplete the reaction, the mixture is stirred at 80-85° C. for a further2 hours, in the course of which the solids go into solution.Subsequently, the phases are separated. The ethanolamine phase isextracted twice with warm toluene (1 litre each time). The combinedtoluene phases are washed twice with 2 litres each time of water at75-80° C. The toluene phases are dried with sodium sulphate, filteredand subsequently reduced to a volume of approx. 430 ml by distillationunder reduced pressure. Subsequently, 1 litre of tert.-butyl methylether is metered in at 50-55° C. and the mixture is then cooled to 0-5°C. The product is isolated by filtration, washed with tert.-butyl methylether and dried at 60° C. in a drying cabinet.

Yield: 273 g (86% of theory); Melting point: 188 ±3° C.

Analogously to Examples 2 and 3,1-[(3-methylisoquinolin-1-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-((R)-3-aminopiperidin-1-yl)-xanthineis also prepared.

What is claimed is:
 1. A process for preparing(R)-3-(phthalimido)piperidine, comprising: reactingrac-3-aminopiperidine with phthalic anhydride; and precipitating(R)-3-(phthalimido)piperidine by adding D-tartaric acid.
 2. A processfor preparing (S)-3-(phthalimido)piperidine, comprising: reactingrac-3-aminopiperidine with phthalic anhydride; precipitating(S)-3-(phthalimido)piperidine by adding L-tartaric acid.
 3. A processfor preparing (R)-3-(phthalimido)piperidine and(S)-3-(phthalimido)piperidine, comprising: reactingrac-3-aminopiperidine with phthalic anhydride; and precipitating(R)-3-(phthalimido)piperidine by adding D-tartaric acid; andprecipitating (S)-3-(phthalimido)piperidine by adding L-tartaric acid.